Individualized dynamic frailty-tailored therapy (DynaFiT) in elderly patients with newly diagnosed multiple myeloma: a prospective study

It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-024-01569-y.

To the editor Despite a remarkable improvement in the outcome of patients with multiple myeloma (MM), the benefit is considerably less impressive for elderly patients [1,2], mainly because of treatment discontinuation (TD) due to frailty [3][4][5][6].While frailty shows dynamic [7,8], it is challenging to treat elderly patients featured by longitudinal frailty changes.To this end, we conducted a prospective study to investigate the feasibility and benefits of an individualized dynamic frailty-tailored therapy (DynaFiT) in elderly patients with newly diagnosed MM (NDMM).
This study was designed based on real-life practice at our center, which enrolled patients aged ≥ 65 years with NDMM who were transplant-ineligible or had no intent for immediate transplant, with minimal exclusion criteria (see Supplementary Information for Methods in detail).According to the NCCN Guidelines Insights: Multiple Myeloma (version 1.2020), participants received eight 21-day cycles of bortezomib, lenalidomide, and dexamethasone (VRd) for induction, followed by maintenance with Rd.Based on the EMN recommendation [9], treatment intensity was adjusted according to longitudinal changes in the frailty category, defined by the IMWG-FI [10], at the start of each cycle (Fig. S1).Daratumumab was recommended for frail patients [3][4][5].Antibiotic/ antiviral prophylaxis was recommended according to the IMWG's consensus [11].
In summary, we report for the first time, to our knowledge, that the DynaFiT is feasible for elderly patients in real-life practice.It allows timely adjusting of treatment intensity to balance efficacy and safety during treatment according to longitudinal changes in the frailty category to avoid both undertreatment and overtreatment in this heterogeneous population.While the choice of treatment in older patients based on the decision of the physician could be safe and effective [12], the DynaFiT may change the view of managing frail patients, to whom intensive therapy was generally not recommended [10].Moreover, this study may also serve as a prototype for future studies to investigate other regimens in elderly patients with MM.

Fig. 1
Fig. 1 Longitudinal changes of frailty.Changes in the frailty category during induction for patients who were defined as frail (a; patient #4 based on age > 80 years alone), fit (b), and intermediate fit (c) at baseline, as well as who proceeded to maintenance (d).B, baseline; M, maintenance; D, daratumumab; sCR, stringent complete response; CR, complete response; VGPR, very good partial response; PR, partial response

Table 1
Frailty category changes, therapeutic responses, and treatment discontinuation Abbreviations: ORR, overall response rate; sCR, stringent complete response; CR, complete response; VGPR, very good partial response; PR, partial response; MR, minimal response; SD, stable disease; PFS, progression-free survival; OS, overall response; TD, treatment discontinuation; AE, adverse event; PNP-P, peripheral neuropathy grade 2 with pain.a Including four patients with age > 80 years.